Production of new sensory neurons in the vertebrate olfactory system continues throughout adult life. The overall aim of this proposal is to examine several aspects of cell proliferation in olfactory epithelium. Earlier experiments had shown that olfactory cell proliferation can be up- and down-regulated by experimental manipulations. Preliminary data from in vitro experiments show that three growth factors, Epidermal Growth Factor (EGF), Transforming Growth Factor-alpha (TGF-alpha) and amphiregulin (AR), can up-regulate the rate of cell proliferation. These growth factors are members of what is called the EGF family of growth factors. The working hypothesis is that members of the EGF family of growth factors participate in the regulation of mitotic rate in olfactory epithelium. The hypothesis is supported by our biochemical and immunohistochemical data identifying the presence of EGF receptor in basal cells (the mitotic cells) of olfactory epithelium. Both EGF and TGF-alpha are presumed to be ligands for this receptor. This proposal represents a multidisciplinary approach to the study of cellular proliferation in the olfactory sensory epithelium. One aim is to determine whether the EGF family of growth factors and their cognate receptors are functional participants in the regulation of sensory (or supporting) cell proliferation both in vitro and in vivo. Another aim is to test other growth factors their efficacy in enhancing proliferation in olfactory epithelium. A third aim is to use an osmotic micropump in experimental animals to deliver small quantities of growth factor (or antibody vs growth factor) directly to the olfactory mucosa to try to stimulate (or inhibit) cellular proliferation locally. Several techniques, including organ culture, immunohistochemistry, electron microscopy, in situ hybridization and biochemistry will be used in these experiments.